Adapter-Layer RTK Signaling: Basic Understanding & Targeted DrugResistance

描述（由申请人提供）：受体酪氨酸激酶（RTK）在发育和体内平衡期间的细胞反应调节中发挥核心作用，并且调节异常有助于疾病，如癌症。RTK靶向疗法已成功应用于癌症治疗，但效果有限，因为非靶向RTK的活性可使细胞产生抗性。虽然冗余信号现在被认为是获得性和先天性抗性的常见机制，但对抗性至关重要的确切信号，以及它是否在癌症背景中是保守的或变化的，尚未得到解决。RTK导致一组共同的下游信号，但在非常不同的定量组合，并在其能力不同，赋予抗性的上下文依赖性的方式。如果我们要开发更好的疗法来克服这种冗余，那么对耐药性的基本、严格的理解是必要的。TAM受体（Tyro3、AXL、MerTK）是RTK家族，由于其在肿瘤抗性和转移中的广泛作用而引起人们的兴趣。然而，虽然这些受体的配体已经被确定，但我们甚至缺乏对导致这些受体激活的背景的基本理解。RTK通过自磷酸化和反磷酸化，募集衔接蛋白，然后磷酸化这些衔接蛋白和其他相关蛋白来工作。系统生物学集中在容易测量的因素，如磷酸化，但受体之间的信号传导的比较不容易完成，因为受体之间的磷酸化位点不容易等同。然而，受体结合的衔接子分子的量是一个应该直接可比的量。因此，我计划开发技术来定量测量RTK相互作用，并同时测量细胞内多种潜在相互作用，目的是更完整地捕获来自这些受体的信号。我将使用这些技术结合定量建模来研究受体激活过程中的相互作用，并了解不同的RTK如何提供冗余信号，从而导致靶向癌症治疗耐药性。这些阻力和相互作用模型，然后将被应用到更具体地了解阻力赋予的TAM家庭的RTK。通过开发与适配器相互作用、下游信号传导和肿瘤细胞耐药性相关的配体依赖性和独立信号传导的机制模型，我计划对耐药性进行综合理解。这将提供必要的信息来开发绕过这个问题的治疗方法。

DESCRIPTION (provided by applicant): Receptor tyrosine kinases (RTKs) play a central role in regulation of cell response during development and homeostasis, and dysregulation contributes to diseases such as cancer. RTK-targeted therapies have been applied successfully in cancer treatment though with limited effectiveness as activity of non-targeted RTKs can enable cells to become resistant. While redundant signaling is now appreciated as a common mechanism of acquired and innate resistance, the exact signaling that is essential to resistance, and whether it is conserved or varies across cancer contexts, has not been addressed. RTKs lead to a common set of downstream signals, but in vastly different quantitative combinations, and differ in their ability to confer resistance in a context-dependent manner. A fundamental, rigorous understanding of resistance is necessary if we are to develop better therapies to overcome this redundancy. TAM receptors (Tyro3, AXL, MerTK) are a family of RTKs that have attracted interest for their widespread roles in tumor resistance and metastasis. However, while the ligands for these receptors have been identified, we lack even a basic understanding of the contexts that lead to activation of these receptors. RTKs work by auto- and trans-phosphorylation, recruiting adapter proteins, and then phosphorylating those adapters and other associated proteins. Systems biology has concentrated on easily measurable factors such as phosphorylation, but comparisons of signaling between receptors are not easily accomplished, as phosphosites between receptors do not readily equate. The amount of receptor-bound adapter molecules is one quantity that should be directly comparable however. Thus, I plan to develop techniques to measure RTK interaction quantitatively and across the multiple potential interactions within a cell simultaneously with the intention of more completely capturing signaling from these receptors. I will use these techniques combined with quantitative modeling to examine interactions during receptor activation and understand how different RTKs can provide redundant signaling leading to targeted cancer treatment resistance. These resistance and interaction models will then be applied to more specifically understand resistance conferred by the TAM family of RTKs. Through development of mechanistic models for ligand-dependent and independent signaling, linked to adapter interaction, downstream signaling, and tumor cell resistance, I plan to develop an integrative understanding of resistance. This will provide necessary information to develop therapies bypassing this problem.